The pancreatic beta-cell isoform of KATP channels, consisting of SURI and KIR6.2 subunits, plays a key role in coupling glucose metabolism to membrane electrical activity. Mutations in either subunit can cause a recessive form of neonatal hypoglycemia termed persistent hyperinsulinemic hypoglycemia of infancy, or PHHI. Recent work has shown that both subunits have trafficking signals. SURI and KIR6.2 have endoplasmic reticulum (ER) retention signals, while we have established that the C-terminus of SURI has an additional signal, which is required for surface expression even in the absence of the ER retention signals. The ER retention signals are 'masked' during channel assembly, and together these two sets of signals act as a quality control mechanism to insure that only completely assembled channels, (SUR1/KIR6.2)4, with both nucleotide-binding folds intact reach the cell surface. A number of PHHI mutations truncate SURI; it is proposed that these deletions remove the C-terminal signal and that the SURIAC channels then fail to reach the cell surface, which accounts for the observed loss of channel activity. The nature of these recently discovered trafficking signals, how they function, and what proteins they interact with is not understood. The objective of this application is to study the role of membrane trafficking in the correct surface expression of KATP channels by determining how the SURI C-terminal 'anterograde' signal works, specifically the investigators propose to: 1. Determine if removal of the SURI C-terminal signal results in increased rates of degradation or targeting to different degradation pathways. 2. Identify "receptor(s)" that may mediate the activity of the SURI carboxyl terminus. 3. Examine the behavior of SURI missense mutations that we have shown exhibit trafficking defects. 4. Characterize the order of assembly of KATP channel sub-units.